The objective of this proposal is to investigate the role for insulin-like growth factor I (IGF-I) in the growth regulation of human cancer. IGF-I is a polypeptide hormone expressed by many tissues during normal growth and has been reported to be expressed by cancer cells. However, these reports are difficult to interpret due to the expression of cross-reacting mRNA species with the IGF-I cDNA on Northern analysis. This problem can be circumvented by using the sensitive and specific ribonuclease protection assay to detect IGF-I mRNA. When 45 epithelial cancer cell lines were examined using this technique, only neuroepithelioma and ovarian cancer cell lines were found to express authentic IGF-I mRNA. Since IGF-I is a potent mitogen for these cells, endogenously produced IGF-I could interact with its receptor (type I IGF receptor) and stimulate autocrine growth. Neuroepithelioma cells were found to secrete IGF-I protein. Moreover, antibody blockade of the type I IGF receptor inhibited basal cellular growth. These finding suggest that IGF-I is an important growth factor for neuroepithelioma and that it may act via an autocrine pathway. Neuroepithelioma and ovarian cancer are ideal model systems in which to study growth regulation of solid tumors by IGF-I. If IGF-I is an important growth factor for these cells, then interference with the IGF-I/type I IGF receptor interaction should inhibit tumor growth. This proposal will directly examine this hypothesis by developing methods to block receptor/ligand interactions and inhibit expression of their genes. The possibility that IGF-I mediates autocrine growth will also be addressed. The specific aims are: 1) to determine the frequency of IGF-I expression in ovarian cancer, 2) to inhibit autocrine growth by antagonizing receptor/ligand interactions with IGF-I neutralizing and receptor blocking antibodies delivered extracellularly or intracellularly by microinjection, 3) to inhibit gene expression of IGF-I and its receptor by inducible anti-sense mRNA and anti-sense oligonucleotides and thereby inhibit tumor growth, 4) to develop these anti-IGF-I strategies for the treatment of cancer using an in vivo mouse model of ovarian carcinomatosis. These studies will provide information on the importance of IGF-I in tumor growth regulation and will test the therapeutic potential of this new form of endocrine therapy.